Paul R. Knight

Acute acid aspiration lung injury in the rat: biphasic pathogenesis.

The Purpose of this stud?/ was to develop a reproducible model of acute acid aspiration-induced lung injury in the rat to explore the pathophysiology of aspiration pneumonitis. A biphasic injury pattern was observed with injury peaks at 1 hr and 4 hr. Histologic studies at 4 hr revealed significant increases in neutrophils in the alveolar interstitial space. These studies suggest that acid aspiration results in a biphasic acute injury. We hypothesize that the first phase results from a direct physiochemical process or is mediated via afferent (capsaicin sensitive) nerves or both. The second phase, occurring 2–3 hr later, is mediated by neutrophils and is consistent with an acute inflammatory response.

Brain-derived TNFα mediates neuropathic pain

Abstract Neuropathic pain is a chronic pain state that develops a central component following acute nerve injury. However, the pathogenic mechanisms involved in the expression of this central component are not completely understood. We have investigated the role of brain-associated TNF in the evolution of hyperalgesia in the chronic constriction injury (CCI) model of neuropathic pain. Thermal nociceptive threshold has been assessed in rats (male, Sprague–Dawley) that have undergone loose, chromic gut ligature placement around the sciatic nerve. Total levels of TNF in regions of the brain, spinal cord and plasma have been assayed (WEHI-13VAR bioassay). Bioactive TNF levels are elevated in the hippocampus. During the period of injury, hippocampal noradrenergic neurotransmission demonstrates a decrease in stimulated norepinephrine (NE) release, concomitant with elevated hippocampal TNF levels. Continuous intracerebroventricular (i.c.v.) microinfusion of TNF-antibodies (Abs) starting at four days, but not six days, following ligature placement completely abolishes the hyperalgesic response characteristic of this model, as assessed by the 58°C hot-plate test. Antibody infusion does not decrease spinal cord or plasma levels of TNF. Continuous i.c.v. microinfusion of rrTNFα exacerbates the hyperalgesic response by ligatured animals, and induces a hyperalgesic response in animals not receiving ligatures. Likewise, field-stimulated hippocampal adrenergic neurotransmission is decreased upon continuous i.c.v. microinfusion of TNF. These results indicate an important role of brain-derived TNF, both in the pathology of neuropathic pain, as well as in fundamental pain perception.

Inhibition of interferon stimulation of natural killer cell activity in mice anesthetized with halothane or isoflurane

BackgroundBasal cytotoxic activity of NK cells, a subtype of lymphocytes Involved In the nonspecific immune response to viruses, tumors, and some bacteria, is altered in the postoperative period. The current study examines the effects of halothane and isoflurane on interferon-induced stimulation of NK cell cytotoxicity in vivo and in vitro. MethodsMice were exposed to either anesthetic on days 10, 5, 1, or −1 relative to interferon treatment on day 0. NK cytotoxicity was assessed 24 h later. Similarly, splenic mono-nuclear cells containing NK cells were treated with Interferon, before or after in vitro exposure with either halothane or isoflurane, and cytotoxiclty was determined. ResultsIn vivo, isoflurane or halothane inhibited subsequent interferon-induced NK cell stimulation (>90% and 67%, respectively). No inhibition occurred if interferon was given before anesthetic exposure. Significant inhibition of interferon-induced NK cell stimulation could be observed 11 days after anesthesia. In vitro, both anesthetics inhibited the subsequent stimulation of NK cytotoxicity by interferon, however, cytotoxicity of NK cells treated with interferon before anesthetic exposure was comparable to untreated interferon-stimulated NK cells. ConclusionsHalothane and isoflurane inhibit interferon stimulation of NK cytotoxicity in naive (unstimulated) NK cells of the splenic mononuclear cell pool without affecting the cytotoxicity of previously stimulated (interferon) NK cells. This could occur directly by preventing the NK cell from responding or indirectly by altering other cells in the splenic mononuclear cell pool (T cells, macrophages), which then inhibit NK cell induction.

The role of neutrophils, oxidants, and proteases in the pathogenesis of acid pulmonary injury.

We recently reported a biphasic injury pattern of nonlethal acid aspiration pneumonitis in rats. The first phase consisted of the immediate effects of the direct tissue injury, and the second phase was associated with a neutrophilic inflammatory response. Using this model, the present report examines the possible role of neutrophils, oxidants, and proteases in the pathogenesis of the second phase of this lung injury. Acid aspiration injury was induced by instillation of saline/HCl, pH = 1.25, into the trachea of rats. Lung injury was assessed by measuring the degree of alveolar capillary permeability to 125I-labeled albumin (permeability index [PI]). Rats made neutropenic with polyclonal antineutrophil antibody had a lower PI (0.44 +/- 0.07, P less than 0.05) 6 h after acid aspiration than similarly injured animals with normal whole blood neutrophil counts (PI = 0.85 +/- 0.03). Even though neutrophils appeared necessary for the full development of the lung injury in this model, the administration of different intravenous and/or intratracheal concentrations of either deferoxamine or catalase offered no protection against injury. This suggests that neutrophil oxidants were minimally involved in the injury. Large increases in leukocyte-free serine protease activity (1,477 +/- 438 u/ml, P less than 0.05) were detected in the bronchoalveolar lavage fluid from the saline/HCl, pH = 1.25, injured rats at 6 h postinjury, as compared to saline/HCl, pH = 5.3, treated control animals (2.7 +/- 0.2 u/ml). This study supports the hypothesis that neutrophils are necessary for the full expression of acid-induced lung injury and that the generation of leukocyte-derived oxidants does not appear to be the primary mechanism involved in this injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenesis of gastric particulate lung injury: a comparison and interaction with acidic pneumonitis.

Experimental aspiration pneumonitis studies in general have focused on the pathogenesis of the acidic component of the lung injury, although the injury produced by the particulate component of gastric contents largely has been ignored. The present study compares the inflammatory potential of small gastric particles to acidic lung injury and examines their interaction. Washed and filtered rat gastric food particles, 2–30 μ were resuspended in saline/HCl, pH = 5.3 or 1.25 at different particle densities and instilled intratracheally into anesthetized rats. Nonlethal lung injury was assessed at different times postaspiration by measuring changes in lung permeability and histology. Maximal survival after lung injury in this model occurred at a particle concentration of 40 mg/mL and at a volume of 1.5 mL/kg. Under these conditions, the alveolar capillary leak was less severe during the first 4 h after injury than that seen with a maximal nonlethal acidic injury (1.5 mL/kg, pH = 1.25). However, after 4 h postinjury the alveolar capillary leak increased to levels that were no different from the acidic injury. When the small gastric food particles were suspended in saline/HCl, pH = 1.25, the alveolar capillary leak was increased synergistically. Intratracheal instillation of inert, 10 μ (glass) particles, 40 mg/mL at 1.5 mL/kg, did not result in an increase in lung injury or interact additively or synergistically with acidic saline. Histologically, the small gastric particle injured lungs were associated with focal inflammatory changes as the acidic damage was diffuse. Although rats that received both particulate and acidic material had a much more severe lung injury than with either of these substances alone, particulate injury also induced chronic inflammation with the formation of early granuloma at 48 h postaspiration. This confirms the synergistic effects of a combined acidic and particulate injury on alveolar capillary leakage. These data suggest a critical and interactive role for both acid and small particulate components in the pathogenesis of gastric aspiration pneumonitis.

Aspiration-Induced lung injury

Objective:Aspiration of oropharyngeal or gastric contents into the lower respiratory tract is a common event in critically ill patients and can lead to pneumonia or pneumonitis. Aspiration pneumonia is the leading cause of pneumonia in the intensive care unit and is one of the leading risk factors for acute lung injury and acute respiratory distress syndromes. Despite its frequency, it remains largely a disease of exclusion characterized by ill-defined infiltrates on the chest radiograph and hypoxia. An accurate ability to diagnose aspiration is paramount because different modalities of therapy, if applied early and selectively, could change the course of the disease. This article reviews definitions, diagnosis, epidemiology, pathophysiology, including animal models of aspiration-induced lung injury, and evidence-based clinical management. Additionally, a review of current and potential biomarkers that have been tested clinically in humans is provided. Data Sources:Data were obtained from a PubMed search of the medical literature. PubMed “related articles” search strategies were used. Summary and Conclusions:Aspiration in the intensive care unit is a clinically relevant problem requiring expertise and awareness. A definitive diagnosis of aspiration pneumonitis or pneumonia is challenging to make. Advances in specific biomarker profiles and prediction models may enhance the diagnosis and prognosis of clinical aspiration syndromes. Evidence-based management is supportive, including mechanical ventilation, bronchoscopy for particulate aspiration, consideration of empiric antibiotics for pneumonia treatment, and lower respiratory tract sampling to define pathogenic bacteria that are causative.

Interkingdom Signaling Induces Streptococcus pneumoniae Biofilm Dispersion and Transition from Asymptomatic Colonization to Disease

ABSTRACT Streptococcus pneumoniae is a common human nasopharyngeal commensal colonizing 10% to 40% of healthy individuals, depending on age. Despite a low invasive disease rate, widespread carriage ensures that infection occurs often enough to make S. pneumoniae a leading bacterial cause of respiratory disease worldwide. However, the mechanisms behind transition from asymptomatic colonization to dissemination and disease in otherwise sterile sites remain poorly understood but are epidemiologically strongly linked to infection with respiratory viruses. In this report, we show that infection with influenza A virus and treatment with the resulting host signals (febrile-range temperatures, norepinephrine, extracytoplasmic ATP, and increased nutrient availability) induce the release of bacteria from biofilms in a newly developed biofilm model on live epithelial cells both in vitro and during in vivo colonization. These dispersed bacteria have distinct phenotypic properties different from those of both biofilm and broth-grown, planktonic bacteria, with the dispersed population showing differential virulence gene expression characteristics resulting in a significantly increased ability to disseminate and cause infection of otherwise sterile sites, such as the middle ear, lungs, and bloodstream. The results offer novel and important insights into the role of interkingdom signaling between microbe and host during biofilm dispersion and transition to acute disease. IMPORTANCE This report addresses the mechanisms involved in transition from pneumococcal asymptomatic colonization to disease. In this study, we determined that changes in the nasopharyngeal environment result in the release of bacteria from colonizing biofilms with a gene expression and virulence phenotype different not only from that of colonizing biofilm bacteria but also from that of the broth-grown planktonic bacteria commonly used for pathogenesis studies. The work importantly also identifies specific host factors responsible for the release of bacteria and their changed phenotype. We show that these interkingdom signals are recognized by bacteria and are induced by influenza virus infection, which is epidemiologically strongly associated with transition to secondary pneumococcal disease. As virus infection is a common inducer of transition to disease among species occupying the nasopharynx, the results of this study may provide a basis for better understanding of the signals involved in the transition from colonization to disease in the human nasopharynx. This report addresses the mechanisms involved in transition from pneumococcal asymptomatic colonization to disease. In this study, we determined that changes in the nasopharyngeal environment result in the release of bacteria from colonizing biofilms with a gene expression and virulence phenotype different not only from that of colonizing biofilm bacteria but also from that of the broth-grown planktonic bacteria commonly used for pathogenesis studies. The work importantly also identifies specific host factors responsible for the release of bacteria and their changed phenotype. We show that these interkingdom signals are recognized by bacteria and are induced by influenza virus infection, which is epidemiologically strongly associated with transition to secondary pneumococcal disease. As virus infection is a common inducer of transition to disease among species occupying the nasopharynx, the results of this study may provide a basis for better understanding of the signals involved in the transition from colonization to disease in the human nasopharynx.

The effects of general anesthesia on upper respiratory tract infections in children

A prospective cohort study of 489 pediatric patients was performed to investigate the prevalence of perioperative respiratory complications and symptomology in children presenting for myringotomy with upper respiratory tract infections (UR1s). All children undergoing myringotomy received halothane N2O/O2 anesthesia administered via face mask. Information on complications and respiratory symptoms was obtained from the anesthesia and recovery room records, and by standardized questionnaire. There were no significant differences in perioperative complications between asymptomatic children (1.23%), symptomatic children fulfilling predetermined URI criteria (1.28%), and symptomatic children that did not fulfill the URI criteria (2.38%). In addition, the prevalence and duration of respiratory symptoms was significantly less in children having received anesthesia and surgery than in a matched group of non-anesthetized controls who did not have surgery. Results from this study suggest that there is no increased morbidity for children presenting at minor surgery with acute uncomplicated URIs and who did not require tracheal intubation. In addition, the administration of general anesthesia and surgery to this group of patients was followed by a decrease in both the appearance and duration of a number of respiratory symptoms.

Brain-derived TNFα : involvement in neuroplastic changes implicated in the conscious perception of persistent pain

The pleiotropic cytokine tumor necrosis factor-alpha (TNFalpha) is implicated in the development of persistent pain through its actions in the periphery and in the central nervous system (CNS). Activation of the alpha(2)-adrenergic receptor is associated with modulation of pain, possibly through its autoregulatory effect on norepinephrine (NE) release in the CNS. The present study employs a chronic constriction nerve injury (CCI) pain model to demonstrate the interactive role of presynaptic sensitivity to TNFalpha and the alpha(2)-adrenergic autoreceptor in the pathogenesis of neuropathic pain. Accumulation of TNFalpha is increased initially in a region of the brain containing the locus coeruleus (LC) at day 4 post-ligature placement, followed by an increase in TNFalpha in the hippocampus at day 8 post-ligature placement, coincident with hyperalgesia. Levels of TNFalpha in the thoraco-lumbar spinal cord are also increased at day 8 post-ligature placement. Concurrently, alpha(2)-adrenergic receptor and TNFalpha-induced inhibition of NE release are increased, and stimulated NE release is decreased in superfused hippocampal slices isolated at day 8 post-ligature placement. Stimulated NE release is also decreased in spinal cord slices (lumbar region) from animals undergoing CCI, although in contrast to that which occurs in the hippocampus, alpha(2)-adrenergic receptor inhibition of NE release is not changed. These results indicate an important role that TNFalpha plays in adrenergic neuroplastic changes in a region of the brain that, among its many functions, appears to be a crucial link in the conscious perception of pain. We predict that neuroplastic changes, involving increased functional responses of alpha(2)-adrenergic autoreceptors and increased presynaptic sensitivity to TNFalpha, culminate in decreased NE release in the CNS. These neuroplastic changes provide a mechanism for the role of CNS-derived TNFalpha in the pathogenesis of persistent pain.

Intraoperative respira-tory complications in patients with upper respiratory tract infections

RésuméUne étude rétrospective de 3,585 patients dont ľâge s’éétend de la naissance à 20 ans a été entreprise afin ďinvestiguer la prévalence de complications respiratoires peropératoires chez les patients présentant des symptômes ďune infection des voies aériennes respiratoires supérieures (VRls). II n’y avait aucune difference statistiquement significative concernant les complications étudiées entre les patients asymptomatiques (1.61 pour cent) el symptomatiques (1.64 pour cent). Cependant les patients asymptomatiques ayant eu une URI récente avaient un taux de complications significativement plus élevé (5.31 pour cent, p < 0.05) que les patients asymptomatiques. II n’y avait aucune difference significative dans les complications peropératoires entre les patients intubés ou non intubés. II n’y avait aussi aucune association entre ľagent anesthésique utilisé et la survenue des complications respiratoires peropératoires. Les résultats de cette étude suggérent que les patients avec URI non compliqué ne présentent pas un risque élevé de complications respiratoires peroperatoires. Cependant les patients qui étaient asymptomatiques mats qui avaient une histoire ďURI récente ont démontré une augmentation significative du risque ďapparition de complications peropératoires.